The Role of Exosomal miRNAs in Glioma: Biological Function and Clinical Application

Abstract

Gliomas are complex and heterogeneous central nervous system tumors with poor prognosis. Despite the increasing development of aggressive combination therapies, the prognosis of glioma is generally unsatisfactory. Exosomal microRNA (miRNA) has been successfully used in other diseases as a reliable biomarker and even therapeutic target. Recent studies show that exosomal miRNA plays an important role in glioma occurrence, development, invasion, metastasis, and treatment resistance. However, the association of exosomal miRNA between glioma has not been systemically characterized. This will provide a theoretical basis for us to further explore the relationship between exosomal miRNAs and glioma and also has a positive clinical significance in the innovative diagnosis and treatment of glioma.

Keywords: biomarkers; exosomes; glioma; miRNA; microenvironment.

Figure 1

The formation and release process of exosome miRNA were revealed. (A) The sorting mechanism of exosomal miRNA MiRNA genes are transcribed into primary miRNAs (pri-miRNA) by Pol-II. Then, with the catalytic action of DGCR8 and Drosha complex, pri-RNA are transmitted into pre-miRNA, which are exported out of the nucleus by exportin5 complex. In the cytoplasm, the pre-miRNAs are digested by the Dicer complex into double-stranded miRNAs, which turn to be single-stranded ones, mature miRNAs, in the next step by Helicase. Mature miRNAs are sorted into exosomes via four potential modes: (a) neutral sphingomyelinase 2 (nSMase2)-dependent pathway. (b) miRNAs motif and heterogeneous ribonucleoprotein (hnRNPs)-dependent pathway; (c) miRNAs sequence 3′-terminal-dependent pathway; (d) Y-box binding protein-1 (YBX-1)-dependent pathway. (B) The biogenesis of exosome begins at endosome formation through endocytosis at the plasma membrane, and then, early endosomes maturate to multivesicular bodies (MVB). Exosomes are formed as intraluminal vesicles in MVBs though endosomal sorting complexes required for transport (ESCRT) dependent or independent pathway. Generally, MVBs either fuse with the lysosome for degradation or fuse with the plasma membrane, which results in exosomes secretion. After secretion, exosomes uptake by target cells is mediated by endocytosis, fusion with the plasma membrane, or ligand/receptor interaction.

Figure 2

Roles of glioma-derived exosomes in glioma development. The first general mechanism is glioma cells can communicate with other cells via exosomal miRNAs in the tumor microenvironment. The second general mechanism is that exosomes derived from glioma cells alter the behavior of normal cells, including promoting glioma carcinogenesis, angiogenesis, and drug resistance and helping cancer cell escape from host immune system, and can be useful diagnostic and/or prognostic biomarkers.